Digital Commons Network^™

Structural Basis For Hyperpolarization-Dependent Opening Of Human Hcn1 Channel, Verena Burtscher, Jonathan Mount, Jian Huang, John Cowgill, Yongchang Chang, Kathleen Bickel, Jianhan Chen, Peng Yuan, Baron Chanda

2020-Current year OA Pubs

Hyperpolarization and cyclic nucleotide (HCN) activated ion channels are critical for the automaticity of action potentials in pacemaking and rhythmic electrical circuits in the human body. Unlike most voltage-gated ion channels, the HCN and related plant ion channels activate upon membrane hyperpolarization. Although functional studies have identified residues in the interface between the voltage-sensing and pore domain as crucial for inverted electromechanical coupling, the structural mechanisms for this unusual voltage-dependence remain unclear. Here, we present cryo-electron microscopy structures of human HCN1 corresponding to Closed, Open, and a putative Intermediate state. Our structures reveal that the downward motion of the gating …

Incidence And Risk Factors For New And Recurrent Infarcts In Adults With Sickle Cell Disease, Lori C Jordan, Allison A King, Andria L Ford, Taniya E Varughese, Lisa Garrett, Et Al.

2020-Current year OA Pubs

BACKGROUND: Most adults with sickle cell disease will experience a silent cerebral infarction (SCI) or overt stroke. Identifying patient subgroups with increased stroke incidence is important for future clinical trials focused on stroke prevention. Our 3-center prospective cohort study tested the primary hypothesis that adults with sickle cell disease and SCIs have a greater incidence of new stroke or SCI compared with those without SCI. A secondary aim focused on identifying additional risk factors for progressive infarcts, particularly traditional risk factors for stroke in adults.

METHODS AND RESULTS: This observational study included adults with sickle cell disease and no history …

Structural Characterization Of Ligand Binding And Ph-Specific Enzymatic Activity Of Mouse Acidic Mammalian Chitinase, Roberto Efraín Díaz, Andrew K Ecker, Galen J Correy, Pooja Asthana, Iris D Young, Bryan Faust, Michael C Thompson, Ian B Seiple, Steven Van Dyken, Richard M Locksley, James S Fraser

2020-Current year OA Pubs

Chitin is an abundant biopolymer and pathogen-associated molecular pattern that stimulates a host innate immune response. Mammals express chitin-binding and chitin-degrading proteins to remove chitin from the body. One of these proteins, Acidic Mammalian Chitinase (AMCase), is an enzyme known for its ability to function under acidic conditions in the stomach but is also active in tissues with more neutral pHs, such as the lung. Here, we used a combination of biochemical, structural, and computational modeling approaches to examine how the mouse homolog (mAMCase) can act in both acidic and neutral environments. We measured kinetic properties of mAMCase activity across …

Cancer-Associated Histone H3 N-Terminal Arginine Mutations Disrupt Prc2 Activity And Impair Differentiation, Benjamin A Nacev, Benjamin A Garcia, Et Al.

2020-Current year OA Pubs

Dysregulated epigenetic states are a hallmark of cancer and often arise from genetic alterations in epigenetic regulators. This includes missense mutations in histones, which, together with associated DNA, form nucleosome core particles. However, the oncogenic mechanisms of most histone mutations are unknown. Here, we demonstrate that cancer-associated histone mutations at arginines in the histone H3 N-terminal tail disrupt repressive chromatin domains, alter gene regulation, and dysregulate differentiation. We find that histone H3R2C and R26C mutants reduce transcriptionally repressive H3K27me3. While H3K27me3 depletion in cells expressing these mutants is exclusively observed on the minor fraction of histone tails harboring the mutations, …

Development Of A Method For Making Optimal Decisions For Intervention Flexibility During Implementation (Modifi): A Modified Delphi Study, Stephanie K Brewer, Catherine M Corbin, Ana A Baumann, Shannon Wiltsey Stirman, Janine M Jones, Michael D Pullmann, Aaron R Lyon, Modifi Expert Panel

2020-Current year OA Pubs

BACKGROUND: Intervention adaptation is often necessary to improve the fit between evidence-based practices/programs and implementation contexts. Existing frameworks describe intervention adaptation processes but do not provide detailed steps for prospectively designing adaptations, are designed for researchers, and require substantial time and resources to complete. A pragmatic approach to guide implementers through developing and assessing adaptations in local contexts is needed. The goal of this project was to develop Making Optimal Decisions for Intervention Flexibility during Implementation (MODIFI), a method for intervention adaptation that leverages human centered design methods and is tailored to the needs of intervention implementers working in applied …

Seeding Activity Of Human Superoxide Dismutase 1 Aggregates In Familial And Sporadic Amyotrophic Lateral Sclerosis Postmortem Neural Tissues By Real-Time Quaking-Induced Conversion, Justin K Mielke, Mikael Klingeborn, Eric P Schultz, Erin L Markham, Emily D Reese, Parvez Alam, Ian R Mackenzie, Cindy V Ly, Byron Caughey, Neil R Cashman, Moses J Leavens

2020-Current year OA Pubs

Amyotrophic lateral sclerosis (ALS) is a rapidly progressive neurodegenerative disease with average lifespan of 2-5 years after diagnosis. The identification of novel prognostic and pharmacodynamic biomarkers are needed to facilitate therapeutic development. Metalloprotein human superoxide dismutase 1 (SOD1) is known to accumulate and form aggregates in patient neural tissue with familial ALS linked to mutations in their SOD1 gene. Aggregates of SOD1 have also been detected in other forms of ALS, including the sporadic form and the most common familial form linked to abnormal hexanucleotide repeat expansions in the Chromosome 9 open reading frame 72 (C9ORF72) gene. Here, we report …

A Longitudinal Mri And Tspo Pet-Based Investigation Of Brain Region-Specific Neuroprotection By Diazepam Versus Midazolam Following Organophosphate-Induced Seizures, Brad A Hobson, Douglas J Rowland, Yimeng Dou, Naomi Saito, Zachary T Harmany, Donald A Bruun, Danielle J Harvey, Abhijit J Chaudhari, Joel R Garbow, Pamela J Lein

2020-Current year OA Pubs

Acute poisoning with organophosphorus cholinesterase inhibitors (OPs), such as OP nerve agents and pesticides, can cause life threatening cholinergic crisis and status epilepticus (SE). Survivors often experience significant morbidity, including brain injury, acquired epilepsy, and cognitive deficits. Current medical countermeasures for acute OP poisoning include a benzodiazepine to mitigate seizures. Diazepam was long the benzodiazepine included in autoinjectors used to treat OP-induced seizures, but it is now being replaced in many guidelines by midazolam, which terminates seizures more quickly, particularly when administered intramuscularly. While a direct correlation between seizure duration and the extent of brain injury has been widely reported, …

Prevalence Of Anti-Myelin Oligodendrocyte Glycoprotein Antibodies Across Neuroinflammatory And Neurodegenerative Diseases, Ritu R Trivedi, Angela S Archambault, Clarice Pavlak, Matteo Gastaldi, Claudia Cantoni, Laura Ghezzi, Anne H Cross, Timothy M Miller, Gregory F Wu

2020-Current year OA Pubs

Inflammatory central nervous system (CNS) diseases, such as multiple sclerosis (MS) and myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), are characterized by humoral immune abnormalities. Anti-MOG antibodies are not specific to MOGAD, with their presence described in MS. Autoantibodies may also be present and play a role in various neurodegenerative diseases. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease driven by motor neuron dysfunction. While immune involvement in ALS has been recognized, the presence of antibodies targeting CNS myelin antigens has not been established. We aimed to establish a live cell-based assay for quantification of serum anti-MOG IgG1 in …

Through The Cat-Map Gateway: A Brief History Of Cataract Genetics, Alan Shiels

2020-Current year OA Pubs

Clouding of the transparent eye lens, or cataract(s), is a leading cause of visual impairment that requires surgical replacement with a synthetic intraocular lens to effectively restore clear vision. Most frequently, cataract is acquired with aging as a multifactorial or complex trait. Cataract may also be inherited as a classic Mendelian trait-often with an early or pediatric onset-with or without other ocular and/or systemic features. Since the early 1990s, over 85 genes and loci have been genetically associated with inherited and/or age-related forms of cataract. While many of these underlying genes-including those for lens crystallins, connexins, and transcription factors-recapitulate signature …

A Randomized, Double-Blind, Phase 3 Safety And Efficacy Study Of Ridinilazole Versus Vancomycin For Treatment Of Clostridioides Difficile Infection: Clinical Outcomes With Microbiome And Metabolome Correlates Of Response, Pablo C Okhuysen, Erik R Dubberke, Et Al.

2020-Current year OA Pubs

BACKGROUND: Exposure to antibiotics predisposes to dysbiosis and Clostridioides difficile infection (CDI) that can be severe, recurrent (rCDI), and life-threatening. Nonselective drugs that treat CDI and perpetuate dysbiosis are associated with rCDI, in part due to loss of microbiome-derived secondary bile acid (SBA) production. Ridinilazole is a highly selective drug designed to treat CDI and prevent rCDI.

METHODS: In this phase 3 superiority trial, adults with CDI, confirmed with a stool toxin test, were randomized to receive 10 days of ridinilazole (200 mg twice daily) or vancomycin (125 mg 4 times daily). The primary endpoint was sustained clinical response (SCR), …

Identifying Mage-A4-Positive Tumors For Tcr T Cell Therapies In Hla-A∗02-Eligible Patients, Tianjiao Wang, Ramaswamy Govindan, Et Al.

2020-Current year OA Pubs

T cell receptor (TCR) T cell therapies target tumor antigens in a human leukocyte antigen (HLA)-restricted manner. Biomarker-defined therapies require validation of assays suitable for determination of patient eligibility. For clinical trials evaluating TCR T cell therapies targeting melanoma-associated antigen A4 (MAGE-A4), screening in studies NCT02636855 and NCT04044768 assesses patient eligibility based on: (1) high-resolution HLA typing and (2) tumor MAGE-A4 testing via an immunohistochemical assay in HLA-eligible patients. The HLA/MAGE-A4 assays validation, biomarker data, and their relationship to covariates (demographics, cancer type, histopathology, tissue location) are reported here. HLA-A∗02 eligibility was 44.8% (2,959/6,606) in patients from 43 sites across …

Comorbid Neurotrauma Increases Neurodegenerative-Relevant Cognitive, Motor, And Autonomic Dysfunction In Patients With Rapid Eye Movement Sleep Behavior Disorder: A Substudy Of The North American Prodromal Synucleinopathy Consortium, Jonathan E Elliott, Jennifer Mcleland, Yo-El S Ju, Et Al.

2020-Current year OA Pubs

STUDY OBJECTIVES: Rapid eye movement sleep behavior disorder (RBD) is strongly associated with phenoconversion to an overt synucleinopathy, e.g. Parkinson's disease (PD), Lewy body dementia, and related disorders. Comorbid traumatic brain injury (TBI) and posttraumatic stress disorder (PTSD)-henceforth "neurotrauma" (NT)-increase the odds of RBD by ~2.5-fold and are associated with an increased rate of service-connected PD in Veterans. Thus, RBD and NT are both independently associated with PD; however, it is unclear how NT influences neurological function in patients with RBD.

METHODS: Participants ≥18 years with overnight polysomnogram-confirmed RBD were enrolled between 8/2018 to 4/2021 through the North American Prodromal …

A Systematic Review And Meta-Analysis, Investigating Dose And Time Of Fluvoxamine Treatment Efficacy For Covid-19 Clinical Deterioration, Death, And Long-Covid Complications, Mani Iyer Prasanth, Dhammika Leshan Wannigama, Angela Michelle Reiersen, Premrutai Thitilertdecha, Anchalee Prasansuklab, Tewin Tencomnao, Sirikalaya Brimson, James Michael Brimson

2020-Current year OA Pubs

There have been 774,075,242 cases of COVID-19 and 7,012,986 deaths worldwide as of January 2024. In the early stages of the pandemic, there was an urgent need to reduce the severity of the disease and prevent the need for hospitalization to avoid stress on healthcare systems worldwide. The repurposing of drugs to prevent clinical deterioration of COVID-19 patients was trialed in many studies using many different drugs. Fluvoxamine (an SSRI and sigma-1 receptor agonist) was initially identified to potentially provide beneficial effects in COVID-19-infected patients, preventing clinical deterioration and the need for hospitalization. Fourteen clinical studies have been carried out …

Scaling Up A Brief Alcohol Intervention To Prevent Hiv Infection In Vietnam: A Cluster Randomized, Implementation Trial, Sophia M Bartels, Byron J Powell, Et Al.

2020-Current year OA Pubs

BACKGROUND: Evidence-based interventions (EBIs) often address normative behaviors. If a behavior is also common among clinicians, they may be skeptical about the necessity or effectiveness of an EBI. Alternatively, clinicians' attitudes and behaviors may be misaligned, or they may lack the knowledge and self-efficacy to deliver the EBI. Several EBIs address unhealthy alcohol use, a common and often culturally acceptable behavior. But unhealthy alcohol use may be particularly harmful to people with HIV (PWH). Here, we present an implementation trial using an experiential implementation strategy to address clinicians' knowledge, attitudes, and behaviors. Clinicians receive the experiential intervention before they begin …

Inhibitory Roles Of Apolipoprotein E Christchurch Astrocytes In Curbing Tau Propagation Using Human Pluripotent Stem Cell-Derived Models, Rei Murakami, Hirotaka Watanabe, Hideko Hashimoto, Mayu Kashiwagi-Hakozaki, Tadafumi Hashimoto, Celeste M. Karch, Takeshi Iwatsubo, Hideyuki Okano, Dominantly Inherited Alzheimer Network (Dian)

2020-Current year OA Pubs

Genetic variants in the

An Inducible Genetic Tool To Track And Manipulate Specific Microglial States Reveals Their Plasticity And Roles In Remyelination, Kia M Barclay, Nora Abduljawad, Min Woo Kim, Lu Zhou, Jin Yang, Justin Rustenhoven, Jose A Mazzitelli, Leon C D Smyth, Dvita Kapadia, Simone Brioschi, Wandy Beatty, Jinchao Hou, Naresha Saligrama, Marco Colonna, Jonathan Kipnis, Qingyun Li, Et Al.

2020-Current year OA Pubs

Recent single-cell RNA sequencing studies have revealed distinct microglial states in development and disease. These include proliferative-region-associated microglia (PAMs) in developing white matter and disease-associated microglia (DAMs) prevalent in various neurodegenerative conditions. PAMs and DAMs share a similar core gene signature. However, the extent of the dynamism and plasticity of these microglial states, as well as their functional significance, remains elusive, partly due to the lack of specific tools. Here, we generated an inducible Cre driver line, Clec7a-CreER

Outcomes Of Subsequent Antilymphoma Therapies After Second-Line Axicabtagene Ciloleucel Or Standard Of Care In Zuma-7, Armin Ghobadi, Et Al.

2020-Current year OA Pubs

The optimal management of patients with relapsed/refractory large B-cell lymphoma (LBCL) after disease progression or lack of response to second-line (2L) therapy remains unclear. Here, we report outcomes among patients who received subsequent antilymphoma therapy per investigator discretion separately by their randomized 2L arm in ZUMA-7, namely axicabtagene ciloleucel (axi-cel) vs standard of care (SOC). Progression-free survival (PFS) and overall survival (OS) were calculated from 3L therapy initiation. In the SOC arm, 127 of 179 randomized patients (71%) received 3L therapy. Median PFS among those who received 3L cellular immunotherapy (n = 68) vs those who did not (n = …

Limited Nerve Regeneration Across Acellular Nerve Allografts (Anas) Coincides With Changes In Blood Vessel Morphology And The Development Of A Pro-Inflammatory Microenvironment, Jesús A Acevedo Cintrón, Daniel A Hunter, Lauren Schellhardt, Deng Pan, Susan E Mackinnon, Matthew D Wood

2020-Current year OA Pubs

The use of acellular nerve allografts (ANAs) to reconstruct long nerve gaps (>3 cm) is associated with limited axon regeneration. To understand why ANA length might limit regeneration, we focused on identifying differences in the regenerative and vascular microenvironment that develop within ANAs based on their length. A rat sciatic nerve gap model was repaired with either short (2 cm) or long (4 cm) ANAs, and histomorphometry was used to measure myelinated axon regeneration and blood vessel morphology at various timepoints (2-, 4- and 8-weeks). Both groups demonstrated robust axonal regeneration within the proximal graft region, which continued across …

Tenovin-1, A Selective Sirt1/2 Inhibitor, Attenuates High-Fat Diet-Induced Hepatic Fibrosis Via Inhibition Of Hsc Activation In Zdf Rats, Swati Sharma, Sreevarsha Gali, Amit Kundu, Jae Hyeon Park, Jae-Sung Kim, Hyung Sik Kim

2020-Current year OA Pubs

Type 2 diabetes mellitus (T2DM) increases the risk of non-alcoholic fatty liver disease (NAFLD) progression to advanced stages, especially upon high-fat diet (HFD). HFD-induced hepatic fibrosis can be marked by oxidative stress, inflammation, and activation of hepatic stellate cells. Sirtuin 1/2 (SIRT1/2), NAD-dependent class III histone deacetylases, are involved in attenuation of fibrosis. In our conducted research, TGF-β1-activated LX-2 cells, free fatty acid (FFA)-treated simultaneous co-culture (SCC) cells, and HFD-induced hepatic fibrosis in Zucker diabetic fatty (ZDF) rats, a widely used animal model in the study of metabolic syndromes, were used to evaluate the protective effect of Tenovin-1, a SIRT1/2 …

Relationship Between Sex Biases In Gene Expression And Sex Biases In Autism And Alzheimer's Disease, Stuart B Fass, Bernard Mulvey, Rebecca Chase, Wei Yang, Din Selmanovic, Sneha M Chaturvedi, Eric Tycksen, Lauren A Weiss, Joseph D Dougherty

2020-Current year OA Pubs

BACKGROUND: Sex differences in the brain may play an important role in sex-differential prevalence of neuropsychiatric conditions.

METHODS: In order to understand the transcriptional basis of sex differences, we analyzed multiple, large-scale, human postmortem brain RNA-Seq datasets using both within-region and pan-regional frameworks.

RESULTS: We find evidence of sex-biased transcription in many autosomal genes, some of which provide evidence for pathways and cell population differences between chromosomally male and female individuals. These analyses also highlight regional differences in the extent of sex-differential gene expression. We observe an increase in specific neuronal transcripts in male brains and an increase in immune …

Cis-Regulatory Evolution Of The Recently Expanded Ly49 Gene Family, Changxu Fan, Xiaoyun Xing, Samuel J H Murphy, Jennifer Poursine-Laurent, Heather Schmidt, Bijal A Parikh, Jeesang Yoon, Mayank N K Choudhary, Naresha Saligrama, Sytse J Piersma, Wayne M Yokoyama, Ting Wang

2020-Current year OA Pubs

Comparative genomics has revealed the rapid expansion of multiple gene families involved in immunity. Members within each gene family often evolved distinct roles in immunity. However, less is known about the evolution of their epigenome and cis-regulation. Here we systematically profile the epigenome of the recently expanded murine Ly49 gene family that mainly encode either inhibitory or activating surface receptors on natural killer cells. We identify a set of cis-regulatory elements (CREs) for activating Ly49 genes. In addition, we show that in mice, inhibitory and activating Ly49 genes are regulated by two separate sets of proximal CREs, likely resulting from …

Dna Methylation And Stroke Prognosis: An Epigenome-Wide Association Study, Joan Jiménez-Balado, Carolina Soriano-Tárraga, Et Al.

2020-Current year OA Pubs

BACKGROUND AND AIMS: Stroke is the leading cause of adult-onset disability. Although clinical factors influence stroke outcome, there is a significant variability among individuals that may be attributed to genetics and epigenetics, including DNA methylation (DNAm). We aimed to study the association between DNAm and stroke prognosis.

METHODS AND RESULTS: To that aim, we conducted a two-phase study (discovery-replication and meta-analysis) in Caucasian patients with ischemic stroke from two independent centers (BasicMar [discovery, N = 316] and St. Pau [replication, N = 92]). Functional outcome was assessed using the modified Rankin Scale (mRS) at three months after stroke, being poor …

Dissemination And Implementation Research Coordination And Training To Improve Cardiovascular Health In People Living With Hiv In Sub-Saharan Africa: The Research Coordinating Center Of The Hlb-Simple Alliance, Emmanuel K Tetteh, William Effah, Lisa De Las Fuentes, Karen Steger-May, Charles W Goss, David W Dowdy, Mark D Huffman, Makeda J Williams, Veronica Tonwe, Geetha P Bansal, Elvin H Geng, Victor G Dávila-Román, Treva Rice, Kenneth B Schechtman

2020-Current year OA Pubs

As global adoption of antiretroviral therapy extends the lifespan of People Living with HIV (PLHIV) through viral suppression, the risk of comorbid conditions such as hypertension has risen, creating a need for effective, scalable interventions to manage comorbidities in PLHIV. The Heart, Lung, and Blood Co-morbiditieS Implementation Models in People Living with HIV (HLB-SIMPLe) Alliance has been funded by the National Heart, Lung, and Blood Institute (NHLBI) and the Fogarty International Center (FIC) since September 2020. The Alliance was created to conduct late-stage implementation research to contextualize, implement, and evaluate evidence-based strategies to integrate the diagnosis, treatment, and control of …

Nurturing Care Assets For Food Security: A Community Asset Mapping Approach, Gabriela Buccini, Kaelia Lynn Saniatan, Ana Poblacion, Ana Bauman, Cristina Hernandez, Cali Larrison, Dodds P Simangan, Jyoti Desai, Yvonne Owens Ferguson, Alisa Howard, Melva Thompson-Robinson

2020-Current year OA Pubs

BACKGROUND: Zip codes classified by the Food Insecurity Index with moderate and high food insecurity (FI) risk can be a threat to the health and well-being of children during the first 1,000 days (from pregnancy to 2 years). The presence of nurturing care assets (i.e., stable environments that promote health and nutrition, learning opportunities, security and safety, and responsive relationships) can contribute to supporting families and their communities, and ultimately reduce systemic barriers to food security. We aimed to identify and characterize nurturing care assets in under-resourced communities with moderate and high FI risk.

METHODS: Four steps were used to …

The Burden Of Cardiovascular Disease Attributable To Hypertension In Nigeria: A Modelling Study Using Summary-Level Data, Adedayo E Ojo, Dike B Ojji, Diederick E Grobbee, Mark D Huffman, Sanne A E Peters

2020-Current year OA Pubs

BACKGROUND: Globally, cardiovascular disease (CVD) remains the leading cause of mortality and disability, with hypertension being the single most important modifiable risk factor. Hypertension is responsible for about 18% of global deaths from CVD, of which African regions are disproportionately affected, especially sub-Saharan Africa. This study assessed the burden of major CVD subtypes attributable to hypertension in Nigeria.

METHODS: The population attributable fractions (PAF) for myocardial infarction, all strokes, ischaemic stroke and intracerebral haemorrhagic stroke attributable to hypertension in Nigeria were calculated using published results from the INTERHEART and INTERSTROKE studies and prevalence estimates of hypertension in Nigeria. PAF estimates …

Giant Left Ventricular Aneurysm With Dynamic Right Ventricular Compression And Subsequent End-Stage Heart Failure, Colin A Martz, Jonathan D Moreno, Justin M Vader, Joel D Schilling, Amit Pawale

2020-Current year OA Pubs

We report a case of a patient with a missed anterior myocardial infarction and associated ischemic cardiomyopathy. The patient had a massive true left ventricular aneurysm causing dynamic right ventricular compression, with associated cardiogenic shock, for which a heart transplantation was ultimately performed.

Frontline Assessors' Opinions About Grading Committees In A Medicine Clerkship, Sophia K Lewis, Nathanial S Nolan, Lisa Zickuhr

2020-Current year OA Pubs

BACKGROUND: Collective decision-making by grading committees has been proposed as a strategy to improve the fairness and consistency of grading and summative assessment compared to individual evaluations. In the 2020-2021 academic year, Washington University School of Medicine in St. Louis (WUSM) instituted grading committees in the assessment of third-year medical students on core clerkships, including the Internal Medicine clerkship. We explored how frontline assessors perceive the role of grading committees in the Internal Medicine core clerkship at WUSM and sought to identify challenges that could be addressed in assessor development initiatives.

METHODS: We conducted four semi-structured focus group interviews with …

Evaluation Of Copanlisib In Combination With Eribulin In Triple-Negative Breast Cancer Patient-Derived Xenograft Models, Zhanfang Guo, Jingqin Luo, R Jay Mashl, Jeremy Hoog, Piyush Maiti, Nikki Fettig, Sherri R Davies, Rebecca Aft, Jason M Held, Ramaswamy Govindan, Li Ding, Shunqiang Li, Cornelius Von Morze, Kooresh I Shoghi, Cynthia X Ma, Et Al.

2020-Current year OA Pubs

UNLABELLED: The PI3K pathway regulates essential cellular functions and promotes chemotherapy resistance. Activation of PI3K pathway signaling is commonly observed in triple-negative breast cancer (TNBC). However previous studies that combined PI3K pathway inhibitors with taxane regimens have yielded inconsistent results. We therefore set out to examine whether the combination of copanlisib, a clinical grade pan-PI3K inhibitor, and eribulin, an antimitotic chemotherapy approved for taxane-resistant metastatic breast cancer, improves the antitumor effect in TNBC. A panel of eight TNBC patient-derived xenograft (PDX) models was tested for tumor growth response to copanlisib and eribulin, alone or in combination. Treatment-induced signaling changes were …

Tl1a And Il-18 Synergy Promotes Gm-Csf-Dependent Thymic Granulopoiesis In Mice, Mario Ruiz Pérez, Kodi Ravichandran, Et Al.

2020-Current year OA Pubs

Acute systemic inflammation critically alters the function of the immune system, often promoting myelopoiesis at the expense of lymphopoiesis. In the thymus, systemic inflammation results in acute thymic atrophy and, consequently, impaired T-lymphopoiesis. The mechanism by which systemic inflammation impacts the thymus beyond suppressing T-cell development is still unclear. Here, we describe how the synergism between TL1A and IL-18 suppresses T-lymphopoiesis to promote thymic myelopoiesis. The protein levels of these two cytokines were elevated in the thymus during viral-induced thymus atrophy infection with murine cytomegalovirus (MCMV) or pneumonia virus of mice (PVM). In vivo administration of TL1A and IL-18 induced …

Debriefer Cognitive Load During Traditional Reflective Debriefing Vs. Rapid Cycle Deliberate Practice Interdisciplinary Team Training, Susan Wiltrakis, Ruth Hwu, Sherita Holmes, Srikant Iyer, Nandranie Goodwin, Claire Mathai, Scott Gillespie, Kiran B Hebbar, Nora Colman

2020-Current year OA Pubs

BACKGROUND: Cognitive load impacts performance of debriefers and learners during simulations, but limited data exists examining debriefer cognitive load. The aim of this study is to compare the cognitive load of the debriefers during simulation-based team training (SbTT) with Rapid Cycle Deliberate Practice (RCDP) debriefing and Traditional Reflective Debriefing (TRD). We hypothesize that cognitive load will be reduced during RCDP compared to TRD.

METHODS: This study was part of a large-scale, interdisciplinary team training program at Children's Healthcare of Atlanta Egleston Pediatric Emergency Department, with 164 learners (physicians, nurses, medical technicians, paramedics, and respiratory therapists (RTs)). Eight debriefers (main facilitators …